ABSTRACT Exposure to arsenic (As) is a serious public health concern, contributing to a myriad of diseases including cancer, cardiovascular disease, diabetes, respiratory disease, and neurological outcomes. As exposure during the early stages of brain development has long-lasting effects on neurocognitive function. Although epidemiological studies report that prenatal As exposure is associated with impaired neurodevelopment, the molecular mechanisms underlying the susceptibility of early brain development to As exposure remain poorly understood. Recently, endoplasmic reticulum (ER) stress by accumulation of unfolded proteins in the ER and subsequent activation of unfolded protein response (UPR) have emerged as a potential mechanism for As- mediated adverse neurological outcomes. Our genome-wide CRISPR screen identified novel ER suppressors of As-induced ER stress including microRNA(miR)-124 and indicated that miR-124 is protective against As- induced ER stress/UPR signaling. Interestingly, miR-124 is one of the most abundant miRs in the brain and plays important roles in neural differentiation and proliferation. Using data from existing genome-wide association studies of an environmental epidemiological cohort, we further showed that miR-124 polymorphism significantly associates with neurological outcomes in children, possibly through interaction with As exposure. Based on these studies, we hypothesize that As perturbs ER stress and UPR signaling in neural stem cells to affect neural stem cell function and to impair early brain development. We further hypothesize that miR-124 protects against As exposure-induced perturbation to restore function and homeostasis in neural stem cells. To test these hypotheses, we propose a highly integrative project that combines molecular mechanistic studies in cultured neural stem cells and human environmental and genetic epidemiology in children exposed to As: Aim 1) Investigate the role of As-induced ER stress on neural stem cell function; Aim 2) Elucidate the mechanisms through which miR-124 protects against As toxicity in neural stem cells; Aim 3) Determine the functional association of miR-124 variants with neurodevelopment in children exposed to As. The proposed study will impact the field of environmental health by keying in on the impact of a top priority, ubiquitous toxicant As on early brain development in children. Results from this study will establish As-induced ER stress/UPR signaling as a crucial mechanism for the adverse effects of As on neural stem cell function and neurodevelopment, and may identify small microRNAs as a novel target for preventative and therapeutic interventions against detrimental effects of As exposure in children.